Triazolotriazinones and the use thereof

ABSTRACT

The invention relates to novel triazolotriazinones of the general formula  
                 
and to a method for their production and pharmaceutical use thereof.

The present relates to novel triazolotriazinones, to processes forpreparing them and to their use as medicaments, in particular asinhibitors of cGMP-metabolizing phosphodiesterases.

J. Heterocycl. Chem. (1993), 30(5), 1341-9, J. Heterocycl. Chem. (1984),21(3), 697-9 and Nucleosides Nucleotides (1995), 14(7), 1601-12 describe6-amino-triazolotriazinones which have an antiviral effect.

J. Med. Chem. (1986), 29(11), 2231-5 also describes6-amino-triazolotriazinones as nucleoside analogs having an antitumoreffect. Triazolotriazinones having the substituents described in thepresent invention and having an inhibitory effect againstcGMP-metabolizing phosphodiesterases have not been disclosed.

The compounds according to the invention are potent inhibitors of cyclicguanosine 3′,5′-monophophate-metabolizing phosphodiesterases(cGMP-PDEs). In accordance with the nomenclature of Beavo and Reifsnyder(Trends in Pharmacol. Sci. 11, 150-155, 1990), these phosphodiesterasesare the phosphodiesterase isoenzymes PDE-I, PDE-II and PDE-V.

An increase in the concentration of cGMP can lead to therapeutic,antiaggregatory, antithrombotic, antiproliferative, antivasospastic,vasodilatory, natriuretic and diuretic effects. It can exert an effecton the short-term or long-term modulation of vascular and cardiacinotropy, cardiac rhythm and stimulus conduction in the heart (J. C.Stoclet, T. Keravis, N. Komas and C. Kugnier, Exp. Opin. Invest. Drugs(1995), 4 (11), 1081-1100). Inhibition of the cGMP-PDEs can alsostrengthen erection. These compounds are therefore suitable for treatingerectile dysfunctions.

The present invention now relates to triazolotriazinones of the generalformula (I),

in which

-   R¹ represents straight-chain or branched alkyl having up to 6 carbon    atoms or represents (C₃-C₈)-cycloalkyl,-   R² represents hydrogen or represents straight-chain or branched    alkyl having up to 6 carbon atoms,-   R³ and R⁴ are identical or different and represent hydrogen or    (C₁-C₆)-alkoxy or represent (C₁-C₆)-alkyl which is optionally    substituted, up to 3 times, identically or differently, by hydroxyl,    (C₁-C₅)-alkoxy or phenoxy or by radicals of the formulae    -   in which    -   R⁵, R⁶, R⁷ and R⁸ are identical or different and denote        hydrogen, (C₁-C₆)-alkyl or phenyl, or    -   R⁷ and R⁸, together with the nitrogen atom to which they are        bonded, form a 5- to 6-membered, saturated heterocycle which can        additionally contain a further heteroatom from the series S and        O,    -   and/or (C₁-C₆)-alkyl is, for its part, optionally substituted by        phenyl which is optionally substituted, up to 3 times,        identically or differently, by hydroxyl, (C₁-C₆)-alkoxy or        halogen or by (C₁-C₆)-alkyl which, for its part, is in turn        substituted by hydroxyl or (C₁-C₆)-alkoxy, or phenyl is        optionally substituted by radicals of the formulae —SO₂—NR⁹R¹⁰        or —NR¹¹R¹²,        -   in which        -   R⁹, R¹⁰, R¹¹ and R¹² are identical or different and denote            hydrogen, (C₁-C₆)-alkyl or phenyl, or        -   R¹¹ and R², together with the nitrogen atom to which they            are bonded, form a 5- to 6-membered, saturated heterocycle            which can additionally contain a further heteroatom from the            series S and O, or-   R³ represents hydrogen or (C₁-C₆)-alkyl, and-   R⁴ represents radicals of the formula    -   or    -   represents phenyl which is optionally substituted, up to 3        times, identically or differently, by halogen, (C₁-C₆)-alkoxy or        hydroxyl or by a radical of the formula    -   or by (C₁-C₆)-alkyl which, for its part, can be substituted by        hydroxyl or (C₁-C₆)-alkoxy, or-   R³ and R⁴, together with the nitrogen atom to which they are bonded,    form a radical of the formula    -   in which    -   R¹³ denotes hydrogen, (C₁-C₆)-alkoxycarbonyl,        (C₃-C₆)-cycloalkyl, pyridyl, pyrimidyl or (C₁-C₆)-alkyl which is        optionally substituted by hydroxyl,    -   R¹⁴ and R¹⁵ are identical or different and denote hydrogen,        hydroxyl or (C₁-C₆)-alkyl which is optionally substituted by        hydroxyl or by a radical of the formula —P(O)(OR¹⁸)(OR¹⁹),        -   in which        -   R¹⁸ and R¹⁹ are identical or different and denote hydrogen            or (C₁-C₆)-alkyl, or    -   R¹⁴ and R¹⁵ together form a radical of the formula ═N—OH,    -   R¹⁶ and R¹⁷ are identical or different and denote hydrogen or        (C₁-C₆)-alkyl which is optionally substituted by hydroxyl,        and the salts, N-oxides and isomeric forms thereof.

The compounds according to the invention can exist in stereoisomericforms which either relate to each other as image and mirror image(enantiomers) or which do not relate to each other as image and mirrorimage (diastereomers). The invention relates to both the enantiomers ordiastereomers or their respective mixtures. The racemic forms, as wellas the diastereomers, can be separated into the stereoisomericallyuniform constituents in a known manner.

The substances according to the invention can also be present as salts.Within the context of the invention, preference is given tophysiologically harmless salts.

Physiologically harmless salts can be salts of the compounds accordingto the invention with inorganic or organic acids. Preference is given tosalts with inorganic acids, such as hydrochloric acid, hydrobromic acid,phosphoric acid or sulfuric acid, or salts with organic carboxylic orsulfonic acid, such as acetic acid, maleic acid, fumaric acid, malicacid, citric acid, tartaric acid, lactic acid or benzoic acid, ormethanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid,toluenesulfonic acid or naphthalenedisulfonic acid.

Physiologically harmless salts can equally well be metal or ammoniumsalts of the compounds according to the invention. Particular preferenceis given, for example, to sodium, potassium, magnesium or calcium salts,and also to ammonium salts which are derived from ammonia, or to organicamines, such as ethylamine, di- or triethylamine, di- ortriethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine,lysine, ethylenediamine or 2-phenylethylamine.

(C₃-C₈)-Cycloalkyl and/or (C₃-C₆)-cycloalkyl represents cyclopropyl,cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl. Thosewhich may be mentioned as being preferred are: cyclopropyl, cyclopentyland cyclohexyl.

(C₁-C₆)-Alkyl represents a straight-chain or branched alkyl radicalhaving from 1 to 6 carbon atoms. Those which may be mentioned by way ofexample are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, n-pentyl and n-hexyl. Preference is given to astraight-chain or branched alkyl radical having from 1 to 4 carbonatoms. Particular preference is given to a straight-chain or branchedalkyl radical having from 1 to 3 carbon atoms.

(C₁-C₆)-Alkoxy represents a straight-chain or branched alkoxy radicalhaving from 1 to 6 carbon atoms. Those which may be mentioned by way ofexample are: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, tert-butoxy, n-pentoxy and n-hexoxy. Preference is given to astraight-chain or branched alkoxy radical having from 1 to 4 carbonatoms. Particular preference is given to a straight-chain or branchedalkoxy radical having from 1 to 3 carbon atoms.

Within the context of the invention, (C₁-C₆)-alkoxycarbonyl represents astraight-chain or branched alkoxycarbonyl radical having from 1 to 6carbon atoms. Those which may be mentioned by way of example are:methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyland tert-butoxycarbonyl. Preference is given to a straight-chain orbranched alkoxycarbonyl radical having from 1 to 4 carbon atoms.Particular preference is given to a straight-chain or branchedalkoxycarbonyl radical having from 1 to 3 carbon atoms.

In general, halogen represents fluorine, chlorine, bromine and iodine.Preference is given to fluorine, chlorine and bromine. Particularpreference is given to fluorine and chlorine.

A 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms fromthe series S, O and/or N represents, for example, pyridyl, pyrimidyl,pyridazinyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl orimidazolyl. Preference is given to pyridyl, pyrimidyl, pyridazinyl,furyl and thienyl.

Preference is given to compounds according to the invention of thegeneral formula (I),

in which

-   R¹ represents straight-chain or branched alkyl having up to 5 carbon    atoms, or represents cyclopropyl, cyclopentyl or cyclohexyl,-   R² represents straight-chain or branched alkyl having up to 4 carbon    atoms,-   R³ and R⁴ are identical or different and represent hydrogen or    methoxy or represent (C₁-C₅)-alkyl which is optionally substituted,    up to 3 times, identically or differently, by hydroxyl,    (C₁-C₄)-alkoxy or phenoxy or by groups of the formulae    -   in which    -   R⁵, R⁶, R⁷ and R⁸ are identical or different and denote        hydrogen, (C₁-C₄)-alkyl or phenyl, or    -   R⁷ and R⁸, together with the nitrogen atom to which they are        bonded, form a morpholine, piperidine or pyrrolidine ring,    -   and/or (C₁-C₅)-alkyl is, for its part, optionally substituted by        phenyl which can be optionally substituted, up to 3 times,        identically or differently, by hydroxyl or (C₁-C₄)-alkoxy or by        (C₁-C₄)-alkyl which, for its part, is in turn substituted by        hydroxyl or (C₁-C₄)-alkoxy, or phenyl is optionally substituted        by radicals of the formulae —SO₂—NR⁹R¹⁰ or —NR¹¹R₁₂,        -   in which        -   R⁹, R¹⁰, R¹¹ and R¹² are identical or different and denote            hydrogen, (C₁-C₄)-alkyl or phenyl, or        -   R¹ and R¹², together with the nitrogen atom to which they            are bonded, form a morpholine, piperidine or pyrrolidine            ring, or-   R³ represents hydrogen or (C₁-C₄)-alkyl, and-   R⁴ represents radicals of the formula    -   or    -   represents phenyl which is optionally substituted, up to 3        times, identically or differently, by fluorine, (C₁-C₄)-alkoxy        or hydroxyl, by a radical of the formula    -   or by (C₁-C₄)-alkyl which can, for its part, be substituted by        hydroxyl or (C₁-C₃)-alkoxy, or-   R³ and R⁴, together with the nitrogen atom to which they are bonded,    form a radical of the formula    -   in which    -   R¹³ denotes hydrogen, (C₁-C₄)-alkoxycarbonyl, cyclopentyl,        cyclohexyl, pyridyl, pyrimidyl or (C₁-C₅)-alkyl which is        optionally substituted by hydroxyl,    -   R¹⁴ and R¹⁵ are identical or different and denote hydrogen or        (C₁-C₅)-alkyl which is optionally substituted by hydroxyl or by        a radical of the formula —P(O)(OR¹⁸)(OR¹⁹),        -   in which        -   R¹⁸ and R¹⁹ are identical or different and denote hydrogen,            methyl or ethyl, or    -   R¹⁴ and R¹⁵ together form a radical of the formula ═N—OH,    -   R¹⁶ and R¹⁷ are identical or different and denote hydrogen,        hydroxyl or (C₁-C₃)-alkyl which is optionally substituted by        hydroxyl,        and the salts, N-oxides and isomeric forms thereof.

Particular preference is given to compounds of the general formula (I),

in which

-   R¹ represents straight-chain or branched alkyl having up to 3 carbon    atoms or represents cyclopentyl,-   R² represents straight-chain or branched alkyl having up to 3 carbon    atoms,-   R³ and R⁴ are identical or different and represent hydrogen or    methoxy or represent (C₁-C₄)-alkyl which is optionally substituted,    up to 3 times, identically or differently, by hydroxyl,    (C₁-C₄)-alkoxy or phenoxy or by groups of the formulae    -   in which    -   R⁵, R⁶, R⁷ and R⁸ are identical or different and denote        hydrogen, (C₁-C₃)-alkyl or phenyl, or    -   R⁷ and R⁸, together with the nitrogen atom to which they are        bonded, form a morpholine, piperidine or pyrrolidine ring,    -   and/or (C₁-C₄)-alkyl is, for its part, optionally substituted by        phenyl which is optionally substituted, up to 3 times,        identically or differently, by hydroxyl, (C₁-C₃)-alkoxy or        fluorine or by (C₁-C₃)-alkyl which is for its part in turn        substituted by hydroxyl or (C₁-C₄)-alkoxy, or phenyl is        optionally substituted by radicals of the formulae —SO₂—NR⁹R¹⁰        or —NR¹¹R¹²,        -   in which        -   R⁹, R¹⁰, R¹¹ and R¹² are identical or different and denote            hydrogen, (C₁-C₃)-alkyl or phenyl, or        -   R¹¹ and R¹², together with the nitrogen atom to which they            are bonded, form a morpholine, piperidine or pyrrolidine            ring, or-   R³ represents hydrogen or methyl, and-   R⁴ represents radicals of the formula    -   or    -   represents phenyl which is optionally substituted, up to 3        times, identically or differently, by fluorine, methoxy or        hydroxyl, by a radical of the formula    -   or by (C₁-C₄)-alkyl which, for its part, can be substituted by        hydroxyl or methoxy or ethoxy, or-   R³ and R⁴, together with the nitrogen atom to which they are bonded,    form a radical of the formula    -   in which    -   R¹³ denotes hydrogen, (C₁-C₄)-alkoxycarbonyl, cyclopentyl,        pyrimidyl or (C₁-C₃)-alkyl which is optionally substituted by        hydroxyl,    -   R¹⁴ and R¹⁵ are identical or different and denote (C₁-C₃)-alkyl        which is optionally substituted by hydroxyl or by a radical of        the formula —P(O)(OR⁸)(OR¹⁹),        -   in which        -   R¹⁸ and R¹⁹ denote ethyl, or    -   R¹⁴ and R¹⁵ together form a radical of the formula ═N—OH,    -   R¹⁶ and R¹⁷ are identical or different and denote hydrogen or        (C₁-C₃)-alkyl which is optionally substituted by hydroxyl,        and the salts, N-oxides and isomeric forms thereof.

Very particular preference is given to the compounds which are listed inthe following table: Structure

In addition, a process was found for preparing the compounds accordingto the invention of the general formula (I), which process ischaracterized in thatcompounds of the general formula (II)

in which

-   R¹ and R² have the abovementioned meaning,    is reacted with chlorosulfonic acid (CISO₃H), where appropriate in    inert solvents and where appropriate in the presence of a base, to    give the compounds of the general formula (III)    in which-   R¹ and R² have the abovementioned meaning,    and subsequently reacted with amines of the general formula (IV)    HNR³R⁴  (IV),    in which-   R³ and R⁴ have the abovementioned meaning.

The process according to the invention can be explained, by way ofexample, by the following formula scheme:

Solvents which are suitable for the individual steps are the customaryorganic solvents which are not altered under the reaction conditions.These solvents preferably include ethers, such as diethyl ether,dioxane, tetrahydrofuran or glycol dimethyl ether, or hydrocarbons, suchas benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions,or halogenohydrocarbons, such as dichloromethane, trichloromethane,tetrachloromethane, dichloroethane, trichloroethylene or chlorobenzene,or ethyl acetate, dimethylformamide, hexamethylphosphoric triamide,acetonitrile, acetone, dimethoxyethane or pyridine. It is likewisepossible to use mixtures of the abovementioned solvents.

In general, the reaction temperatures can vary over a relatively widerange. In general, the temperatures employed are in a range of from −20°C. to 200° C., preferably of from 0° C. to 70° C.

In general, the process steps according to the invention are carried outunder standard pressure. However, it is also possible to carry them outunder positive pressure or under negative pressure (e.g. in a range from0.5 to 5 bar).

The reactions can, for example, take place in a temperature range offrom 0° C. to room temperature and under standard pressure.

The compounds of the general formula (II) are novel and can be preparedby preparing, by means of reacting the compounds of the general formula(V)R¹—CO₂H  (V),in which

-   R¹ has the abovementioned meaning,    with thiocarbohydrazide    the compounds of the general formula (VI)    in which-   R¹ has the abovementioned meaning,    then converting these compounds, by reaction with H₂O₂/CH₃CO₂H, into    the compounds of the general formula (VII)    in which-   R¹ has the abovementioned meaning,    and, in a further step, by means of reacting these compounds with    compounds of the general formula (VIII)    in which-   R² has the abovementioned meaning,    preparing the compounds of the general formula (IX)    in which-   R¹ and R² have the abovementioned meaning,    and subsequently converting these compounds, with diethyl carbonate,    into compounds of the general formula (X)    in which-   R¹ and R² have the abovementioned meaning,    and finally cyclizing these compounds by heating to give the    compounds of the general formula (II).

Solvents which are suitable for the individual steps are the customaryorganic solvents which are not altered under the reaction conditions.These solvents preferably include ethers, such as diethyl ether,dioxane, tetrahydrofuran or glycol dimethyl ether, or hydrocarbons, suchas benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions,or halogenohydrocarbons, such as dichloromethane, trichloromethane,tetrachloromethane, dichloroethane, trichloroethylene or chlorobenzene,or ethyl acetate, dimethylformamide, hexamethylphosphoric triamide,acetonitrile, acetone, dimethoxyethane or pyridine. It is likewisepossible to use mixtures of the abovementioned solvents.

In general, the reaction temperatures can vary within a relatively widerange. In general, the temperatures employed are in a range from −20° C.to 200° C., preferably of from 0° C. to 70° C.

The process steps according to the invention are generally carried outunder standard pressure. However it is also possible to carry them outunder positive pressure or under negative pressure (e.g. in a range from0.5 to 5 bar).

The reactions can, for example, take place in a temperature range offrom 0° C. to room temperature and under standard pressure.

The compounds of the general formulae (III), (IX) and (X) are novel andcan be prepared, for example, as described above.

The compounds of the general formulae (IV), (V), (VI), (VII) and (VIII)are known and can be prepared using customary methods.

The compounds according to the invention of the general formula (I)exhibit a valuable pharmacological spectrum of activity which it was notpossible to foresee.

They inhibit either one or several of the c-GMP-metabolizingphosphodiesterases (PDE I, PDE II and PDE V). This leads to an increasein c-GMP. The differing expression of the phosphodiesterases indifferent cells, tissues and organs, as well as the differingsubcellular location of these enzymes, make it possible, in combinationwith the selective inhibitors according to the invention, to address thedifferent cGMP-regulated processes selectively.

In addition, the compounds according to the invention augment the effectof substances such as EDRF (endothelium-derived relaxing factor) and ANP(atrial natriuretic peptide), of nitro vasodilators and all othersubstances which increase the concentration of the cGMP in another waythan phosphodiesterase inhibitors.

The compounds according to the invention of the general formula (I) aretherefore suitable for the prophylaxis and/or treatment of diseases inwhich an increase in the concentration of cGMP is therapeutic, i.e.diseases which are connected with cGMP-regulated processes (in English,usually simply termed cGMP-related diseases). These diseases includecardiovascular diseases, diseases of the urogenital system andcerebrovascular diseases.

Within the meaning of the present inventin, the term “cardiovasculardiseases” covers diseases such as high blood pressure, neuronalhypertension, stable and unstable angina, peripheral and cardiacvascular diseases, arrhythmias, thromboembolic diseases and ischemiassuch as myocardial infarction, stroke, transistory and ischemic attacks,angina pectoris and peripheral circulatory disturbances, and alsoprevention of restenoses following thrombolysis therapy, percutaneoustransluminal angioplasty (PTA), percutaneous transluminal coronaryangioplasties (PTCA) and bypass.

Furthermore, the compounds according to the invention of the generalformula (I) can also have importance for cerebrovascular diseases. Theseinclude, for example, cerebral ischemia, stroke, reperfusion damage,brain trauma, edemas, cerebral thromboses, dementia and Alzheimer'sdisease.

The relaxing effect on smooth musculature makes them suitable fortreating disorders of the urogenital system such as prostate hypertrophyand incontinence and also, in particular, for treating erectiledysfunction and female sexual dysfunction.

Activity of the Phosphordiesterases (PDEs)

The cGMP-stimulatable PDE II, the cGMP-inhibitable PDE III and thecAMP-specific PDE IV were isolated either from porcine heart myocardiumor from bovine heart myocardium. The Ca²⁺-calmodulin-stimulatable PDE Iwas isolated from porcine aorta, porcine brain or, preferably, frombovine aorta. The c-GMP-specific PDE V was obtained from porcine smallintestine, porcine aorta, human blood platelets and, preferably, frombovine aorta. Purification was effected by means of anion exchangechromatography on Pharmacia MonoQ^(R), essentially in accordance withthe method described by M. Hoey and Miles D. Houslay, BiochemicalPharmacology, Vol. 40, 193-202 (1990) and C. Lugman et al. BiochemicalPharmacology Vol. 35 1743-1751 (1986).

The enzyme activity is determined in a 100 μl test mixture, in 20 mMTris/HCl buffer pH 7.5, which contains 5 mM MgCl₂, 0.1 mg of bovineserum albumin/ml and either 800 Bq of ³HcAMP or ³HcGMP. The finalconcentration of the corresponding nucleotides is 10⁻⁶ mol/l. Thereaction is started by adding the enzyme, with the quantity of enzymebeing measured such that approx. 50% of the substrate is transformedduring the incubation time of 30 min. In order to test thecGMP-stimulatable PDE II, ³HcAMP is used as the substrate and 10⁻⁶ molof unlabeled cGMP/l is added to the mixture. In order to test theCa²⁺-calmodulin-dependent PDE I, 1 μM CaCl₂ and 0.1 μM calmodulin areadditionally added to the reaction mixture. The reaction is stopped byadding 100 μl of acetonitrile which contains 1 mM cAMP and 1 mM AMP. 100μl of the reaction mixture are separated by HPLC and the cleavageproducts are determined quantitatively online using a flow-throughscintillation counter. The substance concentration at which the reactionrate is decreased by 50% is measured. The “phosphodiesterase [³H]cAMP-SPA enzyme assay” and the “phosphodiesterase [³H] cGMP-SPA enzymeassay”, supplied by Amersham Life Science, were additionally used fortesting. The test was carried out using the experimental protocolspecified by the manufacturer. The [³H] cAMP-SPA assay was used fordetermining the activity of PDE II, with 10⁻⁶ M cGMP being added to thereaction mixture for the purpose of activating the enzyme. 10⁻⁷ Mcalmodulin and 1 μM CaCl₂ were added to the reaction mixture for thepurpose of measuring PDE I. PDE V was measured using the [³H] cGMP-SPAassay.

In principle, the inhibition of one or more phosphodiesterases of thistype leads to an increase in the concentration of cGMP. As a result, thecompounds are of interest for all therapies in which an increase in theconcentration of cGMP can be assumed to be therapeutic.

The investigation of the cardiovascular effects was carried out onnormotensive rats and on SH rats and on dogs. The substances wereadministered intravenously or orally.

The examination for erection-inducing effects was carried out onconscious rabbits [H. Naganuma, T. Egashira, J. Fuji, Clinical andExperimental Pharmacology and Physiology 20, 177-183 (1993)]. Thesubstances were administered orally or parenterally.

The novel active compounds, and also their physiologically harmlesssalts (e.g. hydrochlorides, maleates or lactates), can be converted, ina known manner, into the customary formulations, such as tablets, coatedtablets, pills, granules, aerosols, syrups, emulsions, suspensions andsolutions, using inert, nontoxic, pharmaceutically suitable carriersubstances or solvents. In this connection, the therapeuticallyeffective compound should in each case be present at a concentration offrom about 0.5 to 90% by weight of the total mixture, i.e. in quantitieswhich are sufficient for achieving the specified dosage range.

The formulations are prepared, for example, by extending the activecompounds with solvents and/or carrier substances, where appropriateusing emulsifiers and/or dispersants, with it being possible, forexample when using water as a diluent, to use organic solvents asauxiliary solvents, where appropriate.

The administration is effected in a customary manner, preferably orally,transdermally or parenterally, for example perlingually, by the buccalroute, intravenously, nasally, rectally or by inhalation.

For use in humans, doses of from 0.001 to 50 mg/kg, preferably 0.01mg/kg-20 mg/kg, are generally administered when administering orally. Adose of 0.001 mg/kg-0.5 mg/kg is expedient when administeringparenterally, for example by way of mucosae, nasally, by the buccalroute or by inhalation.

Despite this, it can be necessary, where appropriate, to depart from theabove-mentioned quantities, specifically in dependence on the bodyweight or the nature of the route of administration, on the individualresponse to the medicament, on the nature of its formulation and on thetime or interval at which the administration takes place. Thus, it canin some cases be sufficient to make do with less than the abovementionedsmallest quantity whereas, in other cases, the abovementioned upperlimit has to be exceeded. When relatively large quantities are beingadministered, it may be advisable to divide up these quantities intoseveral individual doses which are given during the course of the day.

The compounds according to the invention are also suitable for use inveterinary medicine. For uses in veterinary medicine, the compounds, ortheir nontoxic salts, can be administered in a suitable formulation, inaccordance with common veterinary procedures. The veterinarian canestablish the nature of the application, and the dose, in accordancewith the nature of the animal to be treated.

In the following examples of preparing the precursors and end products,it is always necessary, in structural formulae containing one or moreunsaturated valences on the nitrogen atom or oxygen atom, to add ahydrogen.

In other words, in structures containing, for example, a structuralelement “—N—”, what is meant is actually “—NH—”, and in structurescontaining, for example, a structural element “—O”, what is meant isactually “—OH”.

Preparing the Precursors

EXAMPLE I 4-Amino-5-cyclopentyl-4H-1,2,4-triazole-3-thiol

34.29 g (323 mmol) of finely mortared thiocarbohydrazide are suspendedin 38.5 ml (355.3 mmol) of cyclopentanecarboxylic acid and thesuspension is heated at 165° C. for 20 min. During this, the waterproduced in the reaction is distilled off until a yellowish condensateappears. After cooling down, 250 ml of dichloromethane/methanol 95:5 areadded to the suspension and the precipitate is filtered off. Thefiltrate is concentrated and subject to column filtration on silica gel(dichloromethane/methanol 98:2). After drying under high vacuum, theproduct is obtained as a colorless solid.

Yield: 34.37 g, 75% purity (43.3% of theory).

MS (ESI-pos.): m/z (%)=185 (M+H) (53), 184 (M+) (100), 143 (85).

¹H-NMR (200 MHz, CDCl₃): δ=1.58-2.17 (m, 8H); 2.70-2.82 (m, 1H);3.20-3.35 (m, 1H); 4.51 (s, 2H).

EXAMPLE II 3-Cyclopentyl-4H-1,2,4-triazole-4-amine

34.4 g (75% purity, 140 mmol) of the compound from example I areinitially introduced in 250 ml of acetic acid, and 66 ml of 30% hydrogenperoxide solution are added in portions while refluxing. After theaddition has finished, the mixture is stirred for 30 min at reflux andthen concentrated after having been cooled down; the mixture is thenmade alkaline using 3 N sodium hydroxide solution. The aqueous phase isextracted six times with dichloromethane. After the organic phases havebeen combined, they are washed with a little saturated sodium chloridesolution, dried over magnesium sulfate and concentrated. The slightlyyellowish solid which accumulates is crystallized fromdichloromethane/ether.

Yield: 3.99 g (15.4% of theory).

MS (DCI, NH₃): M/Z (%)=153 (M+H) (100).

¹H-NMR (400 MHz, CDCl₃): δ=1.65-1.98 (m, 7H); 2.03-2.12 (m, 2H); 3.27(qui, 1H); 4.86 (s, 2H); 8.10 (s, 1H).

EXAMPLE IIIN-(3-Cyclopentyl-4H-1,2,4-triazol-4-yl)-2-ethoxybenzenecarboximide-amide

The compound from example II is added, as a solid (1.22 g, 8.02 mmol),to a suspension of 0.34 g (60%, 8.42 mmol) of NaH in 24 ml of dry1,4-dioxane (baked-out flask, under argon). The suspension is stirred at90° C. for 30 min before 1.30 g (8.82 mmol) of 2-ethoxybenzonitrile areadded. The resulting suspension is stirred overnight at 90° C. Afterwater has been added, the mixture is extracted (four times) withdichloromethane. The combined organic phases are washed with a littlesaturated sodium chloride solution and dried over magnesium sulfate.After concentrating down to approximately 20 ml, cyclohexane is addedand the solid which is precipitated out is isolated by filtering it off.

Yield: 1.58 g (65.8% of theory).

MS (DCI, NH₃): m/z (%)=300 (M+H) (100).

¹H-NMR (200 MHz, CDCl₃): δ=1.51 (t, 3H); 1.56-2.12 (m, 8H); 3.14 (qui,1H); 4.22 (q, 2H); 6.49 (bs, 2H); 7.02-7.15 (m, 2H); 7.49 (dt, 1H); 8.04(s, 1H); 8.18 (dd, 1H).

EXAMPLE IV Ethyl[(3-cyclopentyl-4H-1,2,4-triazol-4-yl)-imido]-(2-ethoxyphenyl)methyl-carbamate

1.58 g (5.28 mmol) of the compound from example III are added as asolid, and 1.02 ml (8.4 mmol) of diethyl carbonate are added dropwise,to a suspension of 0.23 g (60%, 5.8 mmol) of sodium hydride in 26 ml ofdry 1,4-dioxane (baked-out flask, argon). The suspension is stirredovernight at 90° C. After it has been cooled down, a further 120 mg ofsodium hydride and 1.02 ml of diethyl carbonate are added and themixture is stirred at 90° C. for a further 4 h before it is neutralized,after having been cooled, with 1 N hydrochloric acid solution andsubsequently concentrated in vacuo. The residue is treated with a littlewater and extracted (four times) with dichloromethane. The combinedorganic phases are washed with a little saturated sodium chloridesolution, dried over magnesium sulfate, concentrated and dried underhigh vacuum.

Yield: 2.14 g, 90% purity (98.2% of theory).

MS (DCI, NH₃): m/z (%)=372 (M+H) (100).

EXAMPLE V 3-Cyclopentyl-6-(2-ethoxyphenyl)[1,2,4]triazolo[3,4-f][1,2,4]triazin-8(7H)-one

A solution consisting of 2.14 g (90%, 5.19 mmol) of the compound fromexample IV in 20 ml of 2-ethoxyethanol is heated overnight under reflux.After it has been cooled down, the mixture is subjected to rotaryevaporation under high vacuum and dried on an oil pump. The solidresidue is treated with hot ether and the solid which precipitates outis filtered off and dried under high vacuum.

Yield: 1.367 g (81% of theory).

MS (DCI, NH₃): m/z (%)=326 (M+H) (100).

¹H-NMR (200 MHz, CDCl₃): δ=1.62 (t, 3H); 1.72-2.30 (m, 8H); 3.68 (qui,1H); 4.34 (q, 2H); 7.08-7.21 (m, 2H); 7.04 (dt, 1H); 8.25 (dd, 1H);10.85 (bs, 1H).

EXAMPLE VI3-(3-Cyclopentyl-8-oxo-7,8-dihydro[1,2,4]triazolo[3,4-f][1,2,4]triazin-6-yl)-4-ethoxybenzenesulfonylChloride

683 mg (2.1 mmol) of the compound from example V are introduced inportions into 1.68 ml (25.2 mmol) of ice-cooled chlorosulfonic acid.After having been warmed to room temperature, the mixture is thenstirred overnight. After having been cooled down to 0° C., it is dilutedwith dichloromethane and the whole is poured onto ice water. The organicphase is separated off. The aqueous phase is extracted once again withdichloromethane, after which the organic phases are combined, washedwith a little saturated sodium chloride solution, dried over magnesiumsulfate and evaporated.

Yield: 801 mg (90% of theory).

MS (DCI, NH₃): m/z (%)=424 (M+H) (100).

¹H-NMR (200 MHz, CDCl₃): δ=1.65 (t, 3H); 1.72-2.32 (m, 8H); 3.71 (qui,1H); 4.47 (q, 2H); 7.30 (d, 1H); 8.22 (dd, 1H); 8.77 (d, 1H); 10.76 (bs,1H).

Preparing the Active Compounds

EXAMPLE 13-Cyclopentyl-6-(2-ethoxy-5-{[4-(2-hydroxyethyl)piperazino]sulfonyl}phenyl)-[1,2,4]triazolo[3,4-f][1,2,4]triazin-8-(7H)-one

394 mg (2.8 mmol) of N-hydroxyethylpiperazine and a small spatula tip of4-N-dimethylaminopyridine (DMAP) are added to a suspension consisting of395 mg (0.92 mmol) of the sulfonyl chloride from example VI in 3 ml ofdichloromethane; the resulting clear solution is stirred at roomtemperature before it is diluted, after 7 hours, with dichloromethane,washed with a little water and saturated sodium chloride, dried overmagnesium chloride and concentrated in vacuo. The residue iscrystallized from a little dichloromethane/ether.

Yield: 368 mg (72.5% of theory).

MS (DCI, NH₃): m/z (%)=518 (M+H) (100).

¹H-NMR (200 MHz, CDCl₃): δ=1.62 (t, 3H); 1.68-2.30 (m, 8H); 2.52-2.70(m, 6H); 3.05-3.17 (m, 4H); 3.52-3.71 (m, 3H); 4.49 (q, 2H); 7.22 (d,1H); 7.91 (dd, 1H); 8.43 (bs, 1H); 10.64 (bs, 1H).

EXAMPLE 23-(3-Cyclopentyl-8-oxo-7,8-dihydro[1,2,4]triazolo[3,4-f][1,2,4]triazin-6-yl)-N-(3,4-dimethoxyphenethyl)-4-ethoxy-N-methylbenzenesulfonamide

546 mg (2.8 mmol) of N-methylhomoveratrylamine and a small spatula tipof 4-DMAP are added to a suspension consisting of 395 mg (0.93 mmol) ofthe sulfonyl chloride from example VI in 3 ml of dichloromethane. Theresulting clear solution is stirred at room temperature before it isdiluted, after 7 h, with dichloromethane, washed with 1 N hydrochloricacid solution (twice) and also saturated sodium chloride, dried overmagnesium chloride and concentrated in vacuo. The residue iscrystallized from a little dichloromethane/ether.

Yield: 299 mg (55.1% of theory).

MS (DCI, NH₃): m/z (%)=583 (M+H) (100).

¹H-NMR (200 MHz, CDCl₃): δ=1.63 (t, 3H); 1.68-2.23 (m, 8H); 2.78-2.90(m, 2H); 2.82 (s, 3H); 3.32 (t, 2H); 3.63 (qui, 1H); 3.84 (s, 6H); 4.39(q, 2H); 6.68-6.80 (m, 3H); 7.17 (d, 1H); 7.89 (dd, 1H); 8.49 (d, 1H);10.66 (bs, 1H).

The sulfonamides which are listed in the following tables were prepared,by means of automated parallel synthesis, from the correspondingsulfonyl chloride (example VI) and the corresponding amines inaccordance with one of the three following standard protocols.

The purity of the end products was determined by means of HPLC whilethey were characterized by means of LC-MS measurement. The numericalvalue specified in the % (HPLC) column indicates the content of the endproduct which is characterized by the molar peak. Standard protocol Awas used in the case of amines possessing acid functionalies, standardprotocol B in the case of amines possessing neutral functionalities, andstandard protocol C in the case of amines possessing additional basicfunctionalities.

In the case of compounds which are listed in the following tables andwhich optically exhibit a free nitrogen valency, this latter is to beunderstood, in principle, as being an —NH radical.

Standard Protocol A: Conversion of Amines Possessing AcidFunctionalities

0.05 mmol of amine, 0.042 mmol of sulfonyl chloride and 0.10 mmol ofNa₂CO₃ are introduced initially, and 0.5 ml of a mixture consisting ofTHF/H₂O is pipetted in by hand. After 24 h at RT, 0.5 ml of a 1 M H₂SO₄solution is added and the mixture is filtered through a two-phasecartridge (500 mg of Extrelut (upper phase) and 500 mg of SiO₂, mobilephase ethyl acetate). The product is obtained after concentrating thefiltrate in vacuo.

Standard Protocol B: Conversion of Amines Possessing NeutralFunctionalities

0.125 mmol of amine is introduced initially and 0.03 mmol of sulfonylchloride, as a solution in 1,2-dichloroethane, is pipetted in by thesynthesizer. After 24 h, 0.5 ml of 1 M H₂SO₄ is added to the mixture andthe latter is filtered through a two-phase cartridge (500 mg of Extrelut(upper phase) and 500 mg of SiO₂, mobile phase: ethyl acetate). Thefiltrate is concentrated in vacuo.

Standard Protocol C: Conversion of Amines Possessing BasicFunctionalities

0.05 mmol of amine is introduced initially and 0.038 mmol of sulfonylchloride, as a solution in 1,2-dichloroethane, and 0.05 mmol oftriethylamine, as a solution in 1,2-dichloroethane, are pipetted in bythe synthesizer. After 24 h, 3 ml of saturated NaHCO₃ solution are addedinitially and the reaction mixture is then filtered through a two-phasecartridge. The product is obtained after the filtrate has beenconcentrated in vacuo.

All the reactions are monitorued by thin layer chromatography. If thereaction has not been completed after 24 hours at RT, the mixture isthen heated at 60° C. for a further 12 hours and the experiment issubsequently terminated. HPLC- Ex. MW Area % at No. Structure [g/mol]210 nm Mz + H  3

490.5856 80 491  4

490.5856 94 491  5

490.5856 97 491  6

538.6302 78 539  7

476.55851 95 477  8

538.6302 81 539  9

476.56 88 477 10

462.53142 91 463 11

504.61269 85 505 12

510.57602 87 511 13

524.60 82 525 14

587.68 80 588 15

522.61 97 523 16

524.60 78 525 17

594.69 77 595 18

510.58 92 511 19

540.60 92 541 20

524.60 82 525 21

510.58 85 511 22

528.57 95 529 23

570.63 89 571 24

524.60 82 525 25

462.53 98 463 26

434.48 82 435 27

515.60 86 516 28

490.59 96 491 29

580.71 74 581 30

490.59 97 491 31

533.61 88 534 32

537.65 86 538 33

559.69 75 560 34

504.61 99 505 35

524.60 85 525 36

579.68 70 580 37

517.61 72 518 38

538.61 67 539 39

501.57 50 502 40

462.53 97 463 41

478.53 74 479 42

488.57 96 489 43

492.56 60 493 44

490.59 40 491 45

476.56 60 477 46

524.60 83 525 47

552.66 70 553 48

538.63 69 539 49

504.61 75 505 50

487.58 83 488 51

541.68 84 542 52

501.57 79 502 53

622.69 80 623 54

612.71 70 613 55

460.56 40 461 56

551.63 75 552 57

545.62 79 546 58

517.61 55 518 59

573.68 75 574 60

490.59 61 491 61

501.61 86 502 62

474.54 75 475 63

488.57 77 489 64

474.54 70 475 65

501.61 64 502

1. A novel triazolotriazinone of the general formula (I)

in which R¹ represents straight-chain or branched alkyl having up to 6carbon atoms or represents (C₃-C₈)-cycloalkyl, R² represents hydrogen orrepresents straight-chain or branched alkyl having up to 6 carbon atoms,R³ and R⁴ are identical or different and represent hydrogen or(C₁-C₆)-alkoxy or represent (C₁-C₆)-alkyl which is optionallysubstituted, up to 3 times, identically or differently, by hydroxyl,(C₁-C₅)-alkoxy or phenoxy or by radicals of the formulae

in which R⁵, R⁶, R⁷ and R⁸ are identical or different and denotehydrogen, (C₁-C₆)-alkyl or phenyl, or R⁷ and R⁸, together with thenitrogen atom to which they are bonded, form a 5- to 6-membered,saturated heterocycle which can additionally contain a furtherheteroatom from the series S and O, and/or (C₁-C₆)-alkyl is, for itspart, optionally substituted by phenyl which is optionally substituted,up to 3 times, identically or differently, by hydroxyl, (C₁-C₆)-alkoxyor halogen or by (C₁-C₆)-alkyl which, for its part, is in turnsubstituted by hydroxyl or (C₁-C₆)-alkoxy, or phenyl is optionallysubstituted by radicals of the formulae —SO₂—NR⁹R¹⁰ or —NR¹¹R¹², inwhich R⁹, R¹⁰, R¹¹ and R¹² are identical or different and denotehydrogen, (C₁-C₆)-alkyl or phenyl, or R¹¹ and R¹², together with thenitrogen atom to which they are bonded, form a 5- to 6-membered,saturated heterocycle which can additionally contain a furtherheteroatom from the series S and O, or R³ represents hydrogen or(C₁-C₆)-alkyl, and R⁴ represents radicals of the formula

or represents phenyl which is optionally substituted, up to 3 times,identically or differently, by halogen, (C₁-C₆)-alkoxy or hydroxyl or bya radical of the formula

or by (C₁-C₆)-alkyl which, for its part, can be substituted by hydroxylor (C₁-C₆)-alkoxy, or R³ and R⁴, together with the nitrogen atom towhich they are bonded, form a radical of the formula

in which R¹³ denotes hydrogen, (C₁-C₆)-alkoxycarbonyl,(C₃-C₆)-cycloalkyl, pyridyl, pyrimidyl or (C₁-C₆)-alkyl which isoptionally substituted by hydroxyl, R¹⁴ and R¹⁵ are identical ordifferent and denote hydrogen, hydroxyl or (C₁-C₆)-alkyl which isoptionally substituted by hydroxyl or by a radical of the formula—P(O)(OR¹⁸)(OR¹⁹), in which R¹⁸ and R¹⁹ are identical or different anddenote hydrogen or (C₁-C₆)-alkyl, or R¹⁴ and R¹⁵ together form a radicalof the formula ═N—OH, R¹⁶ and R¹⁷ are identical or different and denotehydrogen or (C₁-C₆)-alkyl which is optionally substituted by hydroxyl,and the salts, N-oxides and isomeric forms thereof.
 2. A noveltriazolotriazinone of the general formula (I) as claimed in claim 1, inwhich R¹ represents straight-chain or branched alkyl having up to 5carbon atoms, or represents cyclopropyl, cyclopentyl or cyclohexyl, R²represents straight-chain or branched alkyl having up to 4 carbon atoms,R³ and R⁴ are identical or different and represent hydrogen or methoxyor represent (C₁-C₅)-alkyl which is optionally substituted, up to 3times, identically or differently, by hydroxyl, (C₁-C₄)-alkoxy orphenoxy or by groups of the formulae

in which R⁵, R⁶, R⁷ and R⁸ are identical or different and denotehydrogen, (C₁-C₄)-alkyl or phenyl, or R⁷ and R⁸, together with thenitrogen atom to which they are bonded, form a morpholine, piperidine orpyrrolidine ring, and/or (C₁-C₅)-alkyl is, for its part, optionallysubstituted by phenyl which can be optionally substituted, up to 3times, identically or differently, by hydroxyl or (C₁-C₄)-alkoxy or by(C₁-C₄)-alkyl which, for its part, is in turn substituted by hydroxyl or(C₁-C₄)-alkoxy, or phenyl is optionally substituted by radicals of theformulae —SO₂—NR⁹R¹⁰ or —NR¹¹R¹², in which R⁹, R¹⁰, R¹¹ and R¹² areidentical or different and denote hydrogen, (C₁-C₄)-alkyl or phenyl, orR¹¹ and R¹², together with the nitrogen atom to which they are bonded,form a morpholine, piperidine or pyrrolidine ring, or R³ representshydrogen or (C₁-C₄)-alkyl, and R⁴ represents radicals of the formula

or represents phenyl which is optionally substituted, up to 3 times,identically or differently, by fluorine, (C₁-C₄)-alkoxy or hydroxyl, bya radical of the formula

or by (C₁-C₄)-alkyl which can, for its part, be substituted by hydroxylor (C₁-C₃)-alkoxy, or R³ and R⁴, together with the nitrogen atom towhich they are bonded, form a radical of the formula

in which R¹³ denotes hydrogen, (C₁-C₄)-alkoxycarbonyl, cyclopentyl,cyclohexyl, pyridyl, pyrimidyl or (C₁-C₅)-alkyl which is optionallysubstituted by hydroxyl, R¹⁴ and R¹⁵ are identical or different anddenote hydrogen or (C₁-C₅)-alkyl which is optionally substituted byhydroxyl or by a radical of the formula —P(O)(OR¹⁸)(OR¹⁹), in which R¹⁸and R¹⁹ are identical or different and denote hydrogen, methyl or ethyl,or R¹⁴ and R¹⁵ together form a radical of the formula ═N—OH, R¹⁶ and R¹⁷are identical or different and denote hydrogen, hydroxyl or(C₁-C₃)-alkyl which is optionally substituted by hydroxyl, and thesalts, N-oxides and isomeric forms thereof.
 3. A noveltriazolotriazinone of the general formula (I) as claimed in claim 1, inwhich R¹ represents straight-chain or branched alkyl having up to 3carbon atoms or represents cyclopentyl, R² represents straight-chain orbranched alkyl having up to 3 carbon atoms, R³ and R⁴ are identical ordifferent and represent hydrogen or methoxy or represent (C₁-C₄)-alkylwhich is optionally substituted, up to 3 times, identically ordifferently, by hydroxyl, (C₁-C₄)-alkoxy or phenoxy or by groups of theformulae

in which R⁵, R⁶, R⁷ and R⁸ are identical or different and denotehydrogen, (C₁-C₃)-alkyl or phenyl, or R⁷ and R⁸, together with thenitrogen atom to which they are bonded, form a morpholine, piperidine orpyrrolidine ring, and/or (C₁-C₄)-alkyl is, for its part, optionallysubstituted by phenyl which is optionally substituted, up to 3 times,identically or differently, by hydroxyl, (C₁-C₃)-alkoxy or fluorine orby (C₁-C₃)-alkyl which is for its part in turn substituted by hydroxylor (C₁-C₄)-alkoxy, or phenyl is optionally substituted by radicals ofthe formulae —SO₂—NR⁹R¹⁰ or —NR¹¹R¹², in which R⁹, R¹⁰, R¹¹ and R¹² areidentical or different and denote hydrogen, (C₁-C₃)-alkyl or phenyl, orR¹¹ and R¹², together with the nitrogen atom to which they are bonded,form a morpholine, piperidine or pyrrolidine ring, or R³ representshydrogen or methyl, and R⁴ represents radicals of the formula

or represents phenyl which is optionally substituted, up to 3 times,identically or differently, by fluorine, methoxy or hydroxyl, by aradical of the formula

or by (C₁-C₄)-alkyl which, for its part, can be substituted by hydroxylor methoxy or ethoxy, or R³ and R⁴, together with the nitrogen atom towhich they are bonded, form a radical of the formula

in which R¹³ denotes hydrogen, (C₁-C₄)-alkoxycarbonyl, cyclopentyl,pyrimidyl or (C₁-C₃)-alkyl which is optionally substituted by hydroxyl,R¹⁴ and R¹⁵ are identical or different and denote (C₁-C₃)-alkyl which isoptionally substituted by hydroxyl or by a radical of the formula—P(O)(OR⁸)(OR¹⁹), in which R¹⁸ and R¹⁹ denote ethyl, or R¹⁴ and R¹⁵together form a radical of the formula ═N—OH, R¹⁶ and R¹⁷ are identicalor different and denote hydrogen or (C₁-C₃)-alkyl which is optionallysubstituted by hydroxyl, and the salts, N-oxides and isomeric formsthereof.
 4. A novel triazolotriazinone of the general formula (I) asclaimed in claims 1 to 3 and possessing one of the following structures:Structure


5. A process for preparing triazolotriazinones as claimed in claims 1 to4, characterized in that compounds of the general formula (II)

in which R¹ and R² have the abovementioned meaning, are reacted withchlorosulfonic acid (CISO₃H), where appropriate in inert solvents andwhere appropriate in the presence of a base, to give the compounds ofthe general formula (III)

in which R¹ and R² have the abovementioned meaning, and subsequentlyreacted with amines of the general formula (IV)HNR³R⁴  (IV), in which R³ and R⁴ have the abovementioned meaning.
 6. Acompound of the general formula (I) as claimed in claims 1 to 4 for theprophylaxis and/or treatment of diseases.
 7. A medicament orpharmaceutical composition which comprises at least one compound of thegeneral formula (I) as claimed in one of claims 1 to 4 and also one ormore pharmacologically harmless auxiliary substances and carriersubstances.
 8. A medicament or pharmaceutical composition as claimed inclaim 7 for the prophylaxis and/or treatment of diseases which areconnected to cGMP-regulated processes (cGMP-related diseases).
 9. Amedicament or pharmaceutical composition as claimed in claim 7 or 8 forthe prophylaxis and/or treatment of cardiovascular diseases, diseases ofthe urogenital system and cerebrovascular diseases.
 10. A medicament orpharmaceutical composition as claimed in one of claims 7 to 9 for theprophylaxis and/or treatment of cardiovascular diseases such as highblood pressure, neuronal hypertension, stable and unstable angina,peripheral and cardiac vascular diseases, arrhythmias, thromboembolicdiseases and ischemias such as myocardial infarction, stroke,transistory and ischemic attacks, angina pectoris, peripheralcirculatory disturbances, prevention of restenoses followingthrombolysis therapy, percutaneous transluminal angioplasty (PTA),percutaneous transluminal corony arangioplasties (PTCA) and bypass. 11.A medicament or pharmaceutical composition as claimed in one of claims 7to 9 for the prophylaxis and/or treatment of cerebrovascular diseasessuch as cerebral ischemia, stroke, reperfusion damage, brain trauma,edemas, cerebral thrombosis, dementia and Alzheimer's disease.
 12. Amedicament or pharmaceutical composition as claimed in one of claims 7to 9 for the prophylaxis and/or treatment of diseases of the urogenitalsystem such as prostatate hypertrophy, incontinence and, in particular,erectile dysfunction and female sexual dysfunction.
 13. A medicament orpharmaceutical composition as claimed in one of claims 7 to 12,characterized in that the medicament or the pharmaceutical compositionis administered intravenously or orally.
 14. The use of the compounds ofthe general formula (I) as claimed in one of claims 1 to 4 for producingmedicaments or pharmaceutical compositions for the prophylaxis and/ortreatment of diseases.
 15. The use as claimed in claim 14 for producinga medicament or a pharmaceutical composition for the prophylaxis and/ortreatment of diseases which are connected to cGMP-regulated processes(cGMP-related diseases).
 16. The use as claimed in claim 14 or 15 forproducing a medicament or a pharmaceutical composition for theprophylaxis and/or treatment of cardiovascular diseases, diseases of theurogenital system and cerebrovascular diseases.
 17. The use as claimedin one of claims 14 to 16 for producing a medicament or a pharmaceuticalcomposition for the prophylaxis and/or treatment of cardiovasculardiseases such as high blood pressure, neuronal hypertension, stable andunstabile angina, peripheral and cardiac vascular diseases, arrhythmias,thromboembolic diseases and ischemias such as myocardial infarction,stroke, transistory and ischemic attacks, angina pectoris, peripheralcirculatory disturbances, prevention of restenoses followingthrombolysis therapy, percutaneous transluminal angioplasty (PTA),percutaneous transluminal coronary angioplasties (PTCA) and bypass. 18.The use as claimed in one of claims 14 to 16 for producing a medicamentor a pharmaceutical composition for the prophylaxis and/or treatment ofcerebrovascular diseases such as cerebral ischemia, stroke, reperfusiondamage, brain trauma, edemas, cerebral thrombosis, dementia andAlzheimer's disease.
 19. The use as claimed in one of claims 14 to 16for producing a medicament or a pharmaceutical composition for theprophylaxis and/or treatment of diseases of the urogenital system suchas prostate hypertrophy, incontinence and, in particular, erectiledysfunction and female sexual dysfunction.
 20. The use as claimed in oneof claims 14 to 19, characterized in that the medicaments orcompositions are administered intravenously or orally.